Developing Synthetic Actin Toxins for the Treatment of Metastatic Cancers
Metastasis is the leading cause of cancer related deaths and new therapies that disrupt the metastatic process are urgently needed. The actin cytoskeleton is very dynamic structure required for cancer cell invasion and metastasis but has yet to be targeted effectively. Here, we focus on “actin addiction” of metastatic cancers that reflects their dependence on actin polymerization into filamentous-actin (F-actin) based protrusions to invade and metastasize. Human Epidermal Growth Factor-2 (HER2) is a driver and clinical target in cancers with high rates of metastasis. Despite the improvements in therapies targeting HER2, many tumors develop resistance and still progress to metastatic disease. We predict that F-actin disrupting drugs may complement existing cancer therapies. Here, we tested a series of synthetic analogs of Mycalolide B (Myc B), a marine macrolide toxin that severs F-actin, for their effects on SKOV3 ovarian cancer cells. A lead analog, BVP-02-013, was identified as its increased cytotoxicity caused dose dependent suppression of directional migration and invasion kinetics in SKOV3 cells. Live cell imaging of SKOV3 cells expressing a Life-Act GFP reporter showed that this analog severs cellular F-actin into large aggregates within minutes of treatment at doses in the low µM range. Like Myc B, treatments with BVP-02-013 caused loss of leading-edge protrusions and extracellular matrix degradation by invadopodia in SKOV3 cells. These results imply that synthetic Myc B analogs have potential as novel anti-cancer drugs and will provide a rationale to continue the development of actin toxin-based Antibody Drug Conjugates that will deliver actin severing payloads to complement the cytostatic effects of existing HER2 inhibitors.